Abstract

Cough is a common symptom of respiratory disease. Assessment
of antitussives has relied mainly on animal studies and clinical trials in
which recording of natural cough is difficult. This thesis describes the use
of ultrasonically nebulized distilled water (UNOW) to induce cough in man.
Investigation of the chemosensitivity of this response identified that
extremes of pH, a chloride concentration below 75mmol/l, but not changes
in osmolarity induce cough which reflects afferent rapidly adapting
recep~or sensitivity in animal studies. Inhaled beta-adrenergic and
anticholinergic bronchodilators, which inhibit cough in asthma, markedly
reduced UNOW-induced cough in both healthy and asthmatic volunteers.
Bronchoconstriction with inhaled leukotriene 04, which constricts both
asthmatic and non-asthmatic airways, also caused coughing. Inhibition of
bronchoconstriction either specifically or non-specifically resulted in
inhibition of cough. Nedocromil sodium and the diuretic, frusemide, but
not the commonly prescribed opiate, codeine, exhibited antitussive
activity. Cough was also induced by inhalation of the C-fibre stimulants,
capsaicin and prostaglandin E2 (PGE2), which was characterised by
studies of adaptation, cross-adaptation and antitussives. UNOW and
PGE2, but not capsaicin, exhibited rapid adaptation of cough. Crossadaptation,
however, did not occur suggesting distinct mechanisms of
cough mediation. Nedocromil inhibited capsaicin-induced cough but not
PGE2-induced cough, while fenoterol did not affect either challenge.
Oxitropium, which inhibited UNOW-induced cough, did not reduce cough
associated with upper respiratory tract infection.
Cough can be induced by a variety of inhaled stimuli. These can
identify differences in response which may signal a number of pathways
leading to cough. Antitussive activity may also be specific to individual
challenges. This diversity in response reflects the complex neurological
organisation of cough and may be related to pathological causes of cough.